The present invention relates to a benzoic acid derivative of the formula (I): ##STR2## wherein n is an integer of 0 to 2; R.sub.1 to R.sub.3 which may be the same or different each represents a hydrogen atom, a halogen atom, a lower alkyl group (i.e. C.sub.1 -C.sub.5), a lower alkoxy group (i.e. (C.sub.1 -C.sub.5) or a nitro group; R.sub.4 is a hydroxyl group or the group --NHZ (Z is a hydrogen atom or a lower alkyl group (i.e. C.sub.1 -C.sub.5) or an alkali metal salt thereof.
The benzoic acid derivative of the present invention is useful as an infection control agent.
Among the benzoic acid derivatives of the formula (I), the compounds wherein n is 0 or 1; any one of R.sub.1 to R.sub.3 is 5-chloro, 5-methoxy, or 5-nitro and the remainder is hydrogen; and R.sub.4 is a hydroxyl group; and the compounds wherein n is 0 or 1; and two of R.sub.1 to R.sub.3 are 3,5-dichloro or 3,5-dinitro and the remainder is hydrogen; and R.sub.4 is a hydroxyl group are reported together with their preparation in Tetrahedron Vol. 35, pp. 1869-1881 (1979). However, this reference does not refer to any pharmacological activity of these compounds.
It is known that cytoskeletal proteins function as one of the structure proteins in cytoplasm. The cytoskeletal proteins are classified as microtubules, intermediate filaments and microfibers depending on the diameter size. These cytoskeletal proteins are believed to control, on the basis of their contracting ability, the motility of cells, their migration, the change and retention of their morphology, secretion, phagocytosis, adhesion and the transfer of the receptor on the cell membrane. Furthermore, evidence is being accumulated to suggest the association of cytoskeletal proteins with the growth and differentiation of cells.
The present inventors have obtained 2,2'-thiodibenzoic acid derivatives [i.e., compounds of forumla (I) wherein n=0] by reacting 2-halogenobenzoic acid derivatives of the formula: ##STR3## wherein R.sub.1 to R.sub.3 have the same meanings as defined above; and X is a halogen atom with thiosalicylic acid.
Examples of the starting halogenobenzoic acid derivatives include 2-bromo-3,4,5-trimethoxygenzoic acis, 2-bromo-4,5-dimethoxybenzoic acid, 2,4-dichlorobenzoic acid, 2-iodo-3-methyl-4-chlorobenzoic acid, 2-iodo-4,5-dimethylbenzoic acid, 2-iodo-4,6-dimethylbenzoic acid, 2-iodo-3,4-dimethylbenzoic acid, 2-iodo-3,6-dimethylbenzoic acid, 2-iodo-3,5-dimethylbenzoic acid, 2-iodo-5,6-dimethylbenzoic acid, 2-bromo-4-t-butylbenzoic acid, 2-iodo-5-n-butylbenzoic acid, 2-iodo-5-n-propylbenzoic acid, 2-iodo-5-ethylbenzoic acid, 2-iodo-5-methylbenzoic acid, 2-iodo-3-isopropylbenzoic acid, 2-iodo-3-ethylbenzoic acid, 2-iodo-3-methylbenzoic acid, 2-chloro-4-nitrobenzoic acid, 2-chloro-5-nitrobenzoic acid and 2-chloro-3,5-dinitrobenzoic acid.
The reaction between the 2-halogenobenzoic acid derivatives and thiosalicylic acid is performed at 90.degree. C or higher in the presence of a solvent using an alkali and a metal catalyst. Generally, the reaction is carried out at 100-200.degree. C. for 2-10 hours, and the preferred conditions are 110-130.degree. C and 3-5 hours.
Suitable solvents are nitrobenzene, benzyl alcohol, dimethylformamide, xylene, and a mixture of toluene and dimethyformamide.
For the purposes of the present invention, thiosalicylic acid may be used in excess of the 2-halogenobenzoic acid derivative, and the preferred amount ranges from 1.1 to 1.2 moles per mole of the 2-halogenobenzoic acid. Suitable alkalis include anhydrous potassium carbonate and anhydrous sodium carbonate. Suitable metal catalysts include a metallic copper powder, and metal compounds such as cuprous chloride, cupric chloride, curpous bromide, cupric bromide and curpic acetate.
The 2,2'-thiodibenzoic acid derivative may be converted by a general method to the corresponding alkali metal salt such as sodium or potassiuim salt.
The 2,2'-thiodibenzoic acid derivative [compound of formula (I) wherein n=0] may be oxidized with hydrogen peroxide in formic acid or acetic acid at 25.degree. C. or higher so as to obtain 2,2'-sulfonyldibenzoic acid derivative [compound of formula (I) wherein n=2]. The 2,2'-sulfonyldibenzoic acid derivative may be converted by a general method to the corresponding alkali metal salt such as sodium or potassium salt.
The 2,2'-thiodibenzoic acid derivative [compound of formula (I) wherein n=0] may be converted to an ester derivative [a novel compound of formula (I) wherin n=0 and R.sub.4 =a lower alkoxy group], which is then oxidized with a peracid to obtain a 2,2'-sulfinyldibenzoic acid diester derivative [a novel compound of formula (I) wherein n=1 and R.sub.4 =a lower alkoxy group]. The novel compound may be hydrolyzed to obtain a 2,2'-sulfinyldibenzoic acid [compound of formula (I) wherein n=1, R.sub.4 =OH. The 2,2'-sulfinyldibenzoic acid derivative may be converted to the corresponding alkali metal salt such as sodium or potassium salt by a general method.
Amide derivatives of formula (I) wherein n=0, 1 or 2 and R.sub.4 =NHZ (Z=H or a lower alkyl group) may be synthesized from 2,2'-thiodibenzoic acid derivatives, 2,2'-sulfinyldibenzoic acid derivatives by a general method.
The present invention has been accomplished on the basis of the finding of the inventors that the compounds of formula (I) promote the migrating and phagocytotic abilities of macrophages in association with the cytoskeletal proteins.
The compounds of formula (I) can be formulated by any desirable conventional method with a pharmaceutically acceptable carrier.
For oral administration, the compound of this invention can be formulated into a solid preparation such as a tablets, pills, granules, powder, capsules, or the like, or a liquid preparation such as solution, suspension, emulsion or the like. When the preparation is used for parenteral administration, the preparation is formulated into a suppository, injection, an intravenous drip infusion or the like. When the compound of this invention is formulated into tablets, pills, granules, powder or capsules, pharmaceutical carriers such as starch, sucrose, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium carbonate and the like are preferably used. For preparation of an injection, it is preferred that the compound is dissolved in distilled water or an aqueous solution of a salt such as sodium chloride. For preparation of an intravenous drip infusion, the compound is dissolved in a suitable fluid therapy such as a physiological saline, a glucose-sodium chloride solution or the like. For a suppository, cacao butter, laurin, glycerogelatin, macrogol are preferably used as a base.
The amount of the compound in a formulated preparation is selected so as to be appropriately administered depending on the age and condition of individual patient being treated.
The compound of this invention is preferably administered orally in a daily dose of from 10 mg to 2000 mg/day and parenterally in a daily dose of from 50 mg to 1000 mg/ day.
The compounds of formula (I) of the present invention will exhibit an excellent ability to protect animals with reduced immunological functions from contracting infections. The present invention is hereunder described in greater detail by references to working examples and experiments.